TGF-β在細菌影響胰臟癌惡化所扮演的角色

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TGF-β在细菌影响胰脏癌恶化所扮演的角色

Role of TGF-beta signaling pathway in bacteria-affected pancreatic cancer progression

陈宥任 , 硕士　　导师：詹明修　　

繁体中文

牙周致病菌；胰脏癌；转化生长因子-β ； Porphyromonas gingivalis ； Pancreatic cancer ； Transforming growth factor β

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摘要 │ 参考文献 (70) │ 国际计量

摘要〈TOP〉

胰脏癌是恶性肿瘤之一，五年内存活率只有5-6%，目前缺乏有效的治疗。乙型转化生长因子 (Transforming growth factor-β; TGF-β)为多功能性细胞激素。当TGF-β功能丧失或讯息传递异常突变，将导致细胞异常增生、诱导上皮间质转化 (epithelial-mesenchymal transition; EMT) 及转移。由流行病学、微生物相及本实验室动物实验的研究，牙周致病菌牙龈卟啉菌 (Porphyromonas gingivalis; P.gingivalis) 为胰脏癌的致病因子之一。在动物模式中，我们发现益生菌可抑制小鼠之胰脏癌恶化。本研究主要探讨TGF-β讯息路径是否参与益生菌减少胰脏癌恶化的机制。人类胰脏癌细胞株BxPC-3与P. gingivalis培养液共同作用，我们发现TGF-β讯息路径相关分子包括TGF-β1, Smad2, Smad3, and Smad4显着增加，其磷酸化的Smad2和Smad3也增加。而Smad7蛋白显着降低。为了了解TGF-β讯息路径在P. gingivalis促进胰脏癌进展所扮演的角色，利用LSL-KrasG12D; Pdx-1-Cre (KC) 基因转殖胰脏癌小鼠口腔涂抹P. gingivalis。一个月後，我们发现TGF-β及其下游讯息分子Smad2，Smad3，Smad4在胰腺细胞的细胞质中明显增加。另外也发现TGF-β讯息路径活化之phospho-Smad2和phospho-Smad3则有入细胞核的情况，则Smad7的表现量降低。给予益生菌治疗抑制P. gingivalis处理之胰腺细胞TGF-β讯息路径的活化。已知Smad3会调控PD-1的表现，结果显示口腔涂抹P. gingivalis使PD-1和PD-L1表现增加，而给予益生菌则抑制PD-1和PD-L1的表现。在BxPC-3与P. gingivalis培养液共同作用，也发现PD-1与PD-L1 (及SHP-2) 蛋白表现增加。综合以上结果，我们在活体外及活体内的实验均证实给予P. gingivalis活化TGF-β 与PD-1/PD-L1讯息路径与胰脏癌的恶化程度呈正相关性。重要的是，益生菌会抑制胰脏癌进展之TGF-β讯息路径的活化。未来我们将更进一步来了解P. gingivalis和益生菌透过何种机制来调控TGF-β/Smad与PD-1/PD-L1讯息路径。

并列摘要〈TOP〉

Pancreatic cancer is one of the malignant tumors which survival rate is only 5-6% in 5 years, and has no effective therapeutic strategy.  Transforming growth factor-β(TGF-β) is a multifunctional cytokine that can inhibit cell growth.  Loss of function or mutation of TGF-βwill cause the abnormal proliferation of cells.  According the findings through epidemiological studies, microbiota analysis and our animal studies, the periodontitis pathogen Porphyromonas gingivalis (P. gingivalis) may act as a risk factor of pancreatic cancer.  We also found that oral administration of probiotics could inhibit pancreatic cancer progression in vivo.  In this study, we analyzed whether downregulation of TGF-βsignal pathway play a role of probiotics in the pancreatic cancer suppression.  We found that TGF-βsignaling pathway-associated molecules including TGF-β1, Smad2, Smad3, and Smad4 proteins were significantly increased, and phosphorylation levels of Smad2 and Smad3 were increased too. In addition, protein level of Smad7 protein decreased in P. gingivalis culture broth-treated human pancreatic cancer BxPC-3 cells than non-treated cells in vitro.  To understand whether the TGF-βsignaling pathway play role in the pathogenesis of P. gingivalis–promoted pancreatic cancer progression, LSL-KrasG12D;Pdx-1-Cre (KC) transgenic pancreatic cancer mice were oral smear periodontal pathogens P. gingivalis. After one month, we found that TGF-βand its downstream signaling molecules Smad2, Smad3, Smad4 were significantly increased in the cytoplasm of pancreatic cells. In addition, nucleus translocation of phospho-Smad2 and phospho-Smad3 through TGF-βsignaling pathway activation were found too. Smad7 protein expression were decreased in pancreatic tissues from P. gingivalis-treated KC mice.  On the other hand, probiotic treatment cold reverse the activation of TGF-βpathway by P. gingivalis-treatment.  It has been known that Smad3 control immune check point PD-1 expression.  Our results indicated that P. gingivalis treatment increased, but probiotics treatment suppressed, PD-1 and PD-L1 protein expressions.  The enhancement of protein levels of PD-1 and PD-L1 (also SHP-2) by P. gingivalis treatment were found in P. gingivalis culture broth-treated BxPC-3 cells too.  In conclusion, TGF-βand PD-1/PD-L1 pathway activation were observed after P. gingivalis-treatment in vivo and in vitro and it was correlated with the pancreatic cancer progression.  More importantly, probiotics administration may reverse the activation of TGF-βpathway in the development process of pancreatic cancer.  What are the mechanisms of P. gingivalis and probiotics for regulating TGF-βand PD-1/PD-L1 signal pathway should be clarified in more detail in the future.

参考文献 ( 70 ) 〈TOP〉

1. Craig D. Logsdon & Baoan Ji. The role of protein synthesis and digestive enzymes in acinar cell injury. Nat Rev Gastroenterol Hepatol. 2013 Jun;10(6):362-70
连结：
2. Dhiraj Yadav, Albert B. Lowenfels. The Epidemiology of Pancreatitis and Pancreatic Cancer. Gastroenterology. 2013 Jun; 144(6): 1252-1261.
连结：
3. Huang J, Roosaar A, Axéll T, Ye W. A prospective cohort study on poor oral hygiene and pancreatic cancer risk. Int J Cancer. 2016 Jan 15;138(2):340-347.
连结：
4. Manuel Hidalgo and Daniel D. Von Hoff. Translational therapeutic opportunities in ductal adenocarcinoma of the pancreas. Clin Cancer Res. 2012 Aug 15;18(16):4249-4256.
连结：
5. Dominique S. Michaud and Jacques Izard. Microbiota, Oral Microbiome, and Pancreatic Cancer. Cancer J 2014 May-Jun;20(3):203-206.
连结：

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使用DOI作为永久连结

引用含有DOI的文献

DOI可强化引用精确性、增强学术圈连结，并给予使用者跨平台的良好使用经验，目前在全世界已有超过五千万个对象申请DOI。 如想对DOI的使用与概念有进一步了解，请参考 （ ） 。

DOI可强化引用精确性、增强学术圈连结，并给予使用者跨平台的良好使用经验，目前在全世界已有超过五千万个对象申请DOI。如想对DOI的使用与概念有进一步了解，请参考（）。